ECE2009 Poster Presentations Adrenal (54 abstracts)
Replicating the normal cortisol circadian rhythm using a formulation of modified-release hydrocortisone
Miguel Debono 1 , Cyrus Ghobadi 6 , Amin Rostami-Hodjegan 6 , Hiep Huatan 2 , Mike Campbell 7 , John Newell-Price 1 , Ken Darzy 3 , DeborahP Merke 4 , Wiebke Arlt 5 & Richard Ross 1
1Academic Unit of Diabetes, Endocrinology & Metabolism, University of Sheffield, Sheffield, UK; 2H2 Pharma, Sheffield, UK; 3East and North Hertfordshire NHS Trust, Welwyn Garden City, UK; 4National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA; 5Section Endocrinology, Diabetes & Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK; 6Academic Unit of Clinical Pharmacology, University of Sheffield, Sheffield, UK; 7Health Services Research ScHARR, University of Sheffield, Sheffield, UK.
Background: The adrenal glucocorticoid, cortisol, has a distinct circadian rhythm regulated by the brain’s central pacemaker. This cortisol rhythm acts as a secondary messenger to peripheral tissues and loss of the rhythm is associated with increased morbidity and mortality. This is a specific problem in adrenal insufficiency and congenital adrenal hyperplasia (CAH). Based on pharmacokinetic modelling we have developed a modified-release formulation of hydrocortisone (MR-HC) to test whether it can replicate normal cortisol rhythm.
Methods: Using historical data from normal subjects (n=33) we have defined the parameters of the physiological circadian rhythm of cortisol. We have then tested our MR-HC in healthy volunteers (n=28), defined its pharmacokinetic characteristics, compared these to physiological cortisol levels and modelled an optimal treatment regimen to replace circadian cortisol levels.
Results: The key cortisol concentration and time variables in the physiological cortisol profile were defined as: peak 400 nmol/l (95% reference range 296–540), acrophase (time of peak) 0832 h (95% CI 0759–0905 h), nadir <50 nmol/l (95% reference range 35–64), time of nadir 0018 h (95% CI 2339–0058 h), and quiescent phase 1943–0531 h. All MR-HC formulations tested demonstrated delayed and sustained release with MR-HC 15 mg having a mean (S.E.M.) Cmax 457 (38.4) nmol/l at 7.41 (0.57) hrs after drug. Bioavailability of MR-HC 5, 10, 15 & 30 mg was 100, 79, 86, & 69% that of immediate-release hydrocortisone. By pharmacokinetic modelling we revealed that MR-HC 15–20 mg at 2300 h and 10 mg at 0700 h could replicate normal cortisol circadian rhythm.
Conclusion: We have shown that a modified-release formulation of hydrocortisone has the potential to imitate the physiological cortisol rhythm. The future of hydrocortisone replacement lies in the use of physiological therapy for patients with adrenal insufficiency and congenital adrenal hyperplasia.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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